April 21, 2015 | by Rachel Hall
Investigators working at City of Hope are making many significant inroads against many forms of cancer. To do that, they have to take a variety of approaches.
Molecular oncology researchers focus on abnormal cancer-associated activity in a cell’s nucleus. One especially prominent factor in many breast and ovarian cancers is the BRCA1 tumor suppressor. When BRCA1 activity is compromised, cells cannot properly repair breaks in chromosomal DNA, which encourages the accumulation of even more cancer-causing mutations. In short, this increases a woman's risk of developing breast and ovarian cancer.
In one study published in the Journal of Biological Chemistry, Jeremy Stark, Ph.D., associate professor of the Department of Radiation Biology, reported that biologically speaking, two wrongs can make a right. Stark inactivated factors in a signaling pathway called 53BP1/RNF168 and found that intervention blocked lethal failure in DNA repair caused by mutations in the BRCA1 gene.
Now investigators are proposing that pathway components could serve as diagnostics in predicting effective treatment for BRCA1-mutant tumors. That specific pathway could be targeted therapeutically to rescue normal DNA repair in cells carrying BRCA1 mutations. This discovery could lead to more effective drug regimens for women with BRCA1 mutations.
In another study, Timothy O’Connor, Ph.D., associate chair and professor of Cancer Biology, discovered that BRCA1-deficient cells are highly vulnerable to eradication by a class of anti-cancer drugs called PARP inhibitors used in concert with the drug carboplatin. Collaborative work published in Molecular Cancer Therapeutics by O’Connor and Jeffrey Weitzel, M.D., director of the Division of Clinical Cancer Genetics, reports that these drugs work together to kill cancer cells in BRCA1-associated tumors. Together, they are currently testing this approach in a phase II trial.
Interrupt the signal, interrupt the breast cancer
Emily Wang, Ph.D., co-leader of the Molecular Oncology Program, is exploring how a substance required for normal cell growth is subverted in cancer. The substance is called transforming growth factor β, and Wang analyzed its activity by profiling proteins that bind to its receptor, a protein known as TβRI.
Intriguingly, she discovered that in breast cancer cells expressing the oncogene HER-2, the receptor (which in normal cells sits on a cell’s surface) literally relocates to the nucleus and acquires a brand new function — processing or “clipping” RNA molecules.
This study, published in Molecular & Cell Biology, hints that a cancer-specific location change of venue may promote cancer through abnormal RNA processing. This work suggests that biochemically blocking the protein's journey to the nucleus could neutralize its cancer-associated activity.
How to starve a cancer cell
Although biochemical blocking of a protein's journey to a nucleus may be a complex topic for lay audiences, starvation is not.
Other City of Hope researchers are exploring that option when it comes to tumors. Here's the background: Rapidly dividing tumor cells require constant fueling by a nutrient called glutamine. Thus, one way to shrink a tumor might be to starve it of glutamine — but scientists have not understood how to do that at a molecular level.
Mei Kong, Ph.D., assistant professor of the Department of Cancer Biology, knew that cells ramped up a highly complex enzyme in response to dwindling glutamine supplies. She now knows why: Glutamine deprivation sparks a chain reaction involving one of the enzyme's components that ultimately enables cancer cells to prosper in the midst of a glutamine drought.
This study, published in the high impact journal Molecular Cell, is significant. Knowing how tumor cells misappropriate survival mechanisms used by normal cells could lead to drugs that counter this response.
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